医脉通编译，转载请务必注明出处
第17届ESMO胃肠道肿瘤世界大会上提交的一项研究结果显示，KARS，NRAS，BRAF和PIK3CA基因无突变的转移性结直肠癌（mCRC）患者在一线化疗和抗EGFR单克隆抗体应用后疾病进展，会从持续的抗表皮生长因子受体（EGFR）治疗显著获益。医脉通整理如下：
Fortunato Ciardiello教授（来自意大利Seconda Università degli Studi di Napoli）报告了CAPRI-Goim研究结果，该项研究在FOLFIRI化疗和西妥昔单抗治疗后疾病进展的mCRC患者中，评估了西妥昔单抗联合FOLFOX化疗作为二线治疗的疗效。
CAPRI-GOIM是一项非盈利性，学术的II期试验，招募了340例mCRC和KARS外显子2野生型肿瘤患者（以当地分子病理学实验室评估为依据）。所有患者接受标准一线FOLFIRI+西妥昔单抗治疗，直至疾病进展或出现不可耐受的毒性，如先前的报道一致（参考文献：Ciardiello et al，Annals of Oncology 2014）。
一线治疗后，表现出疾病进展的患者按照1:1随机分为接受二线FOLFOX+西妥昔单抗（组A；n=74）治疗，或者单独的FOLFOX（组B；n=79）治疗。研究的主要终点是无进展生存期（PFS），次要终点是总生存期（OS），缓解率和安全性。
“PFS，缓解率，和OS的最终结果在CAPRI研究的第二部分呈现，评估了所谓的‘进展后’内容，”Ciardiello说。
整体意向性治疗人群的数据分析显示，组A的PFS有优势，但未达到统计学差异；FOLFOX+西妥昔单抗组A的中位PFS是6.4个月，与FOLFOX组B的中位4.5个月进行比较（风险比[HR]，0.81；95% CI 0.58，1.12；log-rank检验，P=0.19）。
“因而，我们对出现这一结果的患者特征进行观察，利用患者原发肿瘤的组织样本开展了基因下一代测序（NGS），”Ciardiello解释说。
研究人员使用离子AmpliSeqTM结肠和肺癌控制，包含22个基因的500个热点突变，以及离子Reporter™软件，在之前有过报道（参考文献：Ciardiello et al, Annals of Oncology 2014; Normanno et al., Annals of Oncology 2015）。在117例（75.6%）患者进行NGS，发现66例患者有“全RAS”野生型肿瘤而在KRAS；NRAS；BRAF；或PIK3CA基因中无突变，51例患者肿瘤携带这些基因中的至少一种。KRAS外显子2突变在约15%的肿瘤中发现，这些肿瘤最初定义为野生型。
检测出两种不同患者群体
“我们发现的最重要信息是，当考虑患者涉及KRAS，NRAS，BRAF和PIK3CA基因时，我们检出两种患者群体：一种是多重野生型和所有四种基因正常，另一种是这些基因至少有一种突变。在这些基因中一种至少有一个突变患者中，会对FOLFOX+西妥昔单抗方案在无进展生存期，缓解率和总生存期上带来不利影响，”Ciardiello评论说。
对于无突变，四重野生型群体经二线西妥昔单抗/FOLFOX治疗显示出PFS显著延长，OS和缓解率有所提高，这种治疗方案在EGFR通路基因突变的患者上有相反作用。西妥昔单抗/FOLFOX证明可显著延长四重野生型肿瘤患者的PFS，而在4个EGFR-依赖基因中任一突变的患者中，组A中位PFS几乎低于是组B的一半。
二线FOLFOX+西妥昔单抗在转移性结直肠癌和一种EGFR-依赖性肿瘤患者进展后是可行的
“这项研究的一个重要发现是，肿瘤多重野生型患者——意味着KRAS，NRAS，BRAF和PIK3CA基因没有突变，更有可能是EGFR-依赖性；实际上，这些患者当给予西妥昔单抗和化疗时，比只给与单纯化疗，会有更好的无进展生存期，风险比0.56，是显著的（P=0.025），缓解率和生存期有所提高，HR0.57（P=0.056），”Ciardiello说。
Andrés Cervantes教授（西班牙，生物医学研究所，Valencia大学，ESMO发言人）未参与该项研究，评论说：“这是对如何给选择的患者分组提供治疗的新认识，这些患者是KRAS，NRAS，BRAF和PIK3CA基因野生型，可以在进展后接受相同的抗EGFR抗体和化疗的变化。在意向治疗分析中，这种治疗没有获益，然而没有突变的患者受益于这种方案。”
“这是一个新的发现，即这些患者可以从同一抗体再次治疗中获益，”Cervantes评论道。
结论
“CAPRI是首个在转移性结直肠癌患者中评估西妥昔单抗在进展后作为二线治疗的研究，是一项随机2期研究。结果显示多重野生型KRAS，NRAS，BRAF和PIK3CA基因肿瘤可能从化疗联合西妥昔单抗获益，同时与单纯化疗相比较，显示出更优的无进展生存期，缓解率，和总生存期，”Ciardiello评论说。
Ciardiello继续道，“值得注意的是，这些结果产生了一个非常重要的信号需要在一项更大型，随机，3期研究中进一步探讨，即肿瘤进展后，通过识别患者肿瘤是EGFR依赖型的患者，在二线切换化疗方案时持续的抗-EGFR治疗是可行的；通过识别KRAS，NRAS，BRAF和PIK3CA基因野生型状态也能确定患者对这种治疗的响应。”
原文摘要
Cetuximab beyond progression in RAS wild type (WT) metastatic colorectal cancer (mCRC): the CAPRI-GOIM randomized phase II study of FOLFOX versus FOLFOX plus cetuximab（摘要号LBA-09）
Introduction：Cetuximab in combination with chemotherapy (CT) is a standard treatment for mCRC with KRAS and NRAS (“all RAS”) WT tumours. No data are available on the role of continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression after first line therapy with CT plus anti-EGFR monoclonal antibody. This study evaluates the efficacy of cetuximab plus CT as second line treatment for patients (pts) with mCRC who progressed after CT plus cetuximab.
Methods：In the non profit, academic CAPRI-GOIM trial (Eudract 2009-014041-81), 340 mCRC pts with KRAS exon 2 WT tumour, as assessed by local molecular pathology laboratory, were treated in first line with FOLFIRI plus cetuximab until disease progression or unacceptable toxicity, as previously reported (Ciardiello et al, Annals of Oncology 2014). After first line therapy progression, pts were treated with FOLFOX plus cetuximab (Arm A) or FOLFOX (Arm B) in a 1:1 randomized phase II study. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), response rate and safety. Archival tissue samples from primary tumours were centrally assessed by next generation sequencing (NGS) with the Ion AmpliSeq Colon and Lung cancer panel (500 hotspot mutations in 22 genes) by using Ion Reporter™ Software, as previously reported (Ciardiello et al, Annals of Oncology 2014; Normanno et al., Annals of Oncology 2015).
Results：From February 2010 to September 2014, 153 pts (intention to treat population, ITT) were randomized (74 pts in arm A and 79 pts in arm B). Baseline patient and disease characteristics were well balanced between arms. Median PFS of the ITT population was 6.4 months for FOLFOX plus cetuximab and 4.5 months for FOLFOX (HR=0.81; 95% CI 0.58–1.12; log-rank test, p =0.19). NGS was performed in 117/153 (76.5%) cases. Seventy-five out of 117 pts had “all RAS” WT tumours, whereas a KRAS (exon 2, 3 or 4) or a NRAS (exon 2, 3 or 4) mutation was found in the tumour of 42 pts. KRAS exon 2 mutation were detected in approximately 15% of tumours that were originally defined as WT by local pathology assessment by Sanger sequencing or RT-PCR confirming the results that were previously reported by Ciardiello et al. (Annals of Oncology 2014). Median PFS for the “all RAS” WT population was 6.8 months for arm A and 5.5 months for arm B (HR=0.80; 95% CI 0.50–1.29; log-rank test, p=0.36). Median PFS in the RAS mutated population was 2.7 months for arm A and 4.1 months for arm B (HR=1.53; 95% CI 0.79–2.96; log-rank test, p=0.2). Furthermore, in 66 out of 117 pts,tumours had no mutation in KRAS, NRAS, BRAF, or PIK3CA genes (“quadruple” WT), whereas in 51 out of 117 pts, a mutation in at least one of these genes was found. Median PFS of the “quadruple” WT population was 6.9 months for arm A and 5.3 months for arm B (HR=0.56; 95% CI 0.33–0.94; log-rank test, p =0.025). Median PFS of the mutated (any mutation in KRAS, NRAS, BRAF and/or PIK3CA genes) population was 2.7 months for arm A and 4.4 months for arm B (HR=1.70; 95% CI 0.94–3.05; log-rank test, p=0.07).
Conclusions：This is the first study to demonstrate that in mCRC pts, whose tumours have no mutation in KRAS, NRAS, BRAF and PIK3CA genes, FOLFOX plus cetuximab therapy significantly prolongs PFS as compared to FOLFOX alone, after progressing from FOLFIRI plus cetuximab first line treatment. On the contrary, a detrimental effect of the combination of FOLFOX plus cetuximab is observed in patients whose tumors are mutated for any of the KRAS, NRAS, BRAF and/or PIK3CA genes. Continuing EGFR inhibition by switching the CT backbone is a potential therapeutic strategy that could be further evaluated in a randomized phase III study in mCRC pts with an EGFR-dependent tumour
